THE ROLE OF CYCLIC ADENOSINE-MONOPHOSPHATE IN THE SUPPRESSION OF CELLULAR-IMMUNITY AFTER THERMAL-INJURY

Background and Objective: Cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is known to convey inhibitory sign als for T-cell proliferation and function. We investigated the associa tion between this molecule and the profound immunosuppression that acc ompanies thermal injury. Design: Mice were randomized into two groups: one group was subjected to a 20% full-thickness scald burn; the secon d to a sham burn (control). The mice were killed on days 4, 7, or 10 a fter the burn injury and splenocytes were pooled and cultured for 15 m inutes in the presence or absence of prostaglandin E(2) (PGE(2)). Resu lts: Levels of cAMP in splenocytes were significantly elevated on day 7 after burn in the burn group compared with the sham controls (P<.05, Wilcoxon Rank Sum Test). Incubation of splenocytes with PGE(2) resuit ed in significantly greater levels of intracellular cAMP in cells from the burn group compared with controls on days 4, 7, and 10. Incubatio n of normal splenocytes with dibutyryl cAMP in the presence of concana valin A significantly decreased cell proliferation and the production of interleukin-2. The decrease in interleukin-2 production was evident at the level of messenger RNA expression. Stimulation of splenocytes with a combination of phorbol ester and calcium ionophore, bypassing a ll membrane-associated events prior to protein kinase C activation, re versed the inhibitory effects of dibutyryl cAMP. Incubation of splenoc ytes from burned animals with H-8, a selective inhibitor of cAMP-depen dent protein kinases, restored the proliferative response to that of s ham controls on days 4, 7, and 10 after thermal injury. Conclusions: T hese data indicate that elevated levels of intracellular cAMP, combine d with an increased production of cAMP in response to circulating PGE( 2), may play a fundamental role in suppression of the immune response following thermal injury and that cAMP exerts its immunomodulatory eff ects prior to protein kinase C activation.